Pharmaceutical proteins and polypeptides, among other biopharmaceuticals, pose formulation challenges that can be intractable. Pharmaceutical proteins often cannot be administered orally, because they are degraded by the digestive process. Transdermal administration also generally is not suitable for proteins, because they are too large to pass through the skin effectively. Pulmonary delivery has been developed to the extent that one insulin product has been introduced to the market, but with limited success.
Consequently, pharmaceutical proteins typically are administered by injection; but, there are problems in formulating proteins for injection as well. Proteins in conventional solutions generally are unstable. They are prone to degradation, such as deamidation, aggregation and precipitation, from both chemical and physical processes. Aggregation, precipitation, and viscosity are particularly problematic for most proteins, especially at high protein concentrations. Proteins generally are more stable when lyophilized than they are in solution. However, inconvenience and patient compliance limit the successful marketing of lyophilized drug products and the preference for liquid formulations.
Proteins often cannot be formulated at sufficiently high concentrations for injection of effective amounts. In cases where the solubility and/or stability of the protein is limited, products are formulated at lower concentrations and delivered by intravenous infusion. However, high concentration protein-based medicines are desired by both patients and manufacturers. One reason is that is allows smaller volumes of liquid to be administered to an individual. Nevertheless, increasing the protein concentration may result in deleterious effects. The goal of high concentration and lyophilization has been elusive, in part because of deleterious viscoelastic and other properties occurring as concentration increases. Increased concentration sometimes, for instance, increases the tendency to aggregate or form gels, as well as increases the difficulty in administering these solutions through standard subcutaneous syringe and needle configurations.
In one example, antibody and antibody-like therapeutics are inherently difficult to concentrate, likely due in part to the nature of their complementarity determining regions (“CDRs,” further discussed below). And yet, for therapeutic applications, antibody compositions at concentrations above 100 mg/ml or even 200 mg/ml are desirable. Similarly, high concentrations of other proteins commonly used to treat individuals is also desirable, for instance, for those individuals administered proteins either intravenously or subcutaneously.
Developing acceptable protein formulations is particularly challenging at high concentrations, such as those required for injection. Presently, a variety of proteins cannot be stably formulated at high concentrations in solution. Even for those that have been formulated in solution at relatively high concentrations, the solutions are not stable, suffering from aggregation or precipitation, and are too viscous for injection. Consequently, there are many proteins that suffer from sub-optimal formulations or cannot be formulated advantageously for injection at all.
There is, therefore, a need for methods to make improved protein formulations, and for the formulations themselves. In one aspect, there is a need for protein formulations that are stable and have low viscosity. In another aspect, there is a need for protein formulations that are stable and have low viscosity for a protein therapeutic formulation at a high protein concentration for administration. In a further aspect, there is a need for formulations that are stable and have low viscosity for a liquid protein therapeutic formulation at a high protein concentration for administration by injection. Also, there is a need for better systematic methods to develop such formulations.